PARIS HEPATITIS CONFERENCE 2012
30-31 January 2012
What’s new in HCV genotype 2?
Alessandra Mangia
S.Giovanni Rotondo,ITALY
Key issues
•
•
•
•
Epidemiological background
Response rates with Peg/RBV
Does IL28B plays any role?
New therapeutic approaches
HCV genotype 2 prevalence in Europe and Canada
Mean rate
8.2%
9%
27%
M.Conrberg et al 2010
HCV 2 and tx in Italy
HCV genotype distribution in 1604 pts
enrolled into the Prophesys study in Italy
7%
27%
62%
HCV-4
(n=70)
HCV-3
(n=275
HCV-2
(n=478)
HCV-1
(n=777)
4.3%
17%
30%
48%
Prophesys 2 Final analysis
5%
G1
G2
G3
G4
Peg-IFN-a + ribavirin:
incidence of treatment failure
Peg-IFN-a 2a
+ ribavirin1
58%
54%
48%
Peg-IFN-a 2a
+ ribavirin2
24%
Peg-IFN-a 2b
+ ribavirin3
16%
Genotype 1
Peg-IFN: peginterferon
18%
Genotypes 2/3
1. Fried MW, et al. N Engl J Med 2002;347:975–982
2. Hadziyannis S, et al. Ann Intern Med 2004;40:346–355
3. Manns M, et al. Lancet 2001;358:958–965
Demographic characteristics of Italian
pts with HCV 2/3 evaluated in the
interim analysis of the WRITE study
HCV 3
(n=303)
HCV 2
(n=200)
P value
Mean age
(years)
44.2
56.5
0.001
Male gender
71%
46%
0.001
20.5%
10.5%
0.003
Blood transfusion
13%
6%
0.0001
Previous surgery
16%
33%
Unknown
22%
48%
IVDA
56%
6%
Fibrosis stage 4
WRITE STUDY Data on file
Final results from 7163 naive, pts
enrolled in the PROPHESYS study
 To investigate the predictive value of virological
responses by week 2, 4 and 12 on SVR.
 Patients infected with HCV genotype 2 had the highest
rates of on-treatment virological responses and SVR
rates among all groups (71% vs 42% in genotype 1)
 The highest relapse rates occurred among genotype 1
patients and the lowest relapse rates in genotype 2
patients (27% vs 11% in genotype 1)
Marcellin p et al AASLD 2011
PROPHESYS STUDY: Virological response
over time in HCV 2 and 3 patients
On Treatment, EOT and SVR Response
HCV 3
94
100%
92
84
91
88
74
80%
71
61
60%
40%
20%
0%
wk4
wk 12
EOT
SVR
Marcellin P et al AASLD 2011
SVR rates by RVR in HCV-2 pts enrolled in
studies on short or standard tx duration
No of pts
RVR
(%)
SVR in 12/16
weeks (%)
Relapse
(%)
SVR in 24
weeks (%)
Relapse
(%)
150
86
94 (45/50)
6 (3/50)
95 (95/100)
3 (3/100)
455/728
69
81 (196/243)
17 (39/233)
92 (194/212)
5 (10/204)
vonWagner
39
97
95 (18/19)
0.5 (1/19)
95 (18/19)
0.5 (1/19)
Mecenate
116
68
80 (32/40)
3 (1/34)
79 (31/39)
0
Dalgard
85
71
93 (27/29)
7 (2/29)
97 (30/31)
3 (1/31)
Mangia
213
64
87 (89/102)
3 (3/98)
76 (40/53)
3 (1/32)
Yu
Shiffman
Diago,
SVR rates by RVR in HCV-3 pts enrolled in
studies on short or standard tx duration
No of pts
RVR
(%)
SVR in 12/16
weeks (%)
Relapse
(%)
SVR in 24
weeks (%)
Relapse
(%)
408/728
56
84 (236/215)
14 (29/206)
90 (173/193)
7 (13/180)
vonWagner
113
91
76 (39/51)
16(8/52)
75 (39/52)
4 (2/51)
Mecenate
94
68
87 (28/32)
3 (1/29)
69 (22/32)
8 (2/24)
Dalgard
119
70
84 (93/110)
15 (17/110)
92 (106/115)
8 (9/115)
Mangia
70
59
77 (24/31)
14 (4/928)
100 (10/10)
0
Shiffman
Diago,
Rates of non RVR and SVR in pts with HCV2 and HCV-3 who received 24 wks of tx
No of
HCV-2 pts
Non RVR
(%)
SVR after
24 wks in
non
RVR
No of
HCV-3 pts
Non RVR
(%)
SVR after
24 wks in
non
RVR
Yu
150
14
77 (10/13)
NA
NA
NA
Shiffman
728
43
53 (58/109)
727
13
39 (58/150)
Mangia
213
35
78 (45/58)
70
41
41 (9/22)
Mecenate
116
32
60 (22/37)
94
32
60 (18/30)
Dalgard
85
29
75 (15/20)
343
31
56 (54/96)
SNP near IL28B predicts SVR with PR
p = 2.06 x 10–3
p = 4.39 x 10–3
p = 1.37 x 10–28
TT TC CC
TT TC CC
TT TC CC
African
American
Hispanic
SVR (%)
p = 1.06 x 10–25
rs 129760 predicts SVR
TT TC CC
n=102 n=433 n=336
-chromosome 19
-3kb upstream of IL28B
-P=1.37 x10-28 across
all population groups
Caucasian
n=70
n=91
n=30
n=14
n=35
n=26
n=186 n=559 n=392
Combined
SVR
Non-SVR
Ge D, et al. Nature 2009; 461: 399–401
Original study protocol
n=268*
Week 0
Standard-24 (SD)
Variable-12/24 (VD)
PegIFN + ribavirin for 24 weeks
n=68
PegIFN + RBV for 12 or 24 weeks
n=200
Week 4
HCV-RNA -ve
HCV-RNA +ve
Treated for 12 weeks
n=122
Treated for 24 weeks
n=78
Drop out
n=3
Drop out
n=2
Completed
n=120
Week 12
Drop out
n=4
Week 24
Completed
n=64
* 13 patients did not provide informed consent; genotyping failed in 2
Drop out
n=1
Completed
n=74
Mangia EASL 2010
IL28B-type is associated with increased SVR in non-RVR
patients treated with 24 weeks therapy
Mangia EASL 2010
HCV-2
211*
SVR
151
(72%)
SVR in RVR
108/130
(83%)
SVR in noRVR
43/81
(53%)
CC
79 (37%)
60 (76%)
39/47 (83%)
21/32 (66%)
CT
101 (48%)
72 (71%)
57/67 (85%)
15/34 (44%)
TT
31 (15%)
19 (61%)
12/16 (75%)
7/15 (47%)
HCV-2
77^
SVR^
51/58
(88%)
CC
40 (52%)
51%
21/22 (95%)
1/4 (25%)
CT
29 (38%)
NA
NA
0
TT
8 (10%)
NA
NA
0
Mangia et al.
Sarrazin et al
^ p=0.09 SVR vs NR (follow up information were not for available in all patients)
*in 4 patients IL28B was not determinable
SVR^in RVR
SVR^noRVR
IL 28B: clinical implications in
G2 and G3
G2
RVR (+)
No
role for
IL28B
24 wks
If IL28B CC
G3
RVR (-)
If unfavourable IL28B
48 wks?
DAA?
IL28B with the new drugs
SILEN C-1
BMS 790052 +Peg-IFN
Study design
 Design: Phase IIa multicentre, partially blinded, randomised,
stratified for genotype, multiple-dose trial in France, Italy, Sweden
and UK
TVR
(T mono)
Screening
Peg-IFN + RBV
TVR + Peg-IFN + RBV
(triple therapy)
(T/PR)
Peg-IFN + RBV
PBO + Peg-IFN + RBV
(PR)
Peg-IFN + RBV
2 weeks
Follow up
for  24
weeks
after EOT
24 weeks (T mono arm)
22 weeks (T/PR and PR arms)
TVR 750 mg q8h; Peg-IFN alfa-2a 180g/week; RBV 800mg/day
EOT = end of treatment; PBO = placebo
Median HCV RNA decline from
baseline – G2
Time (Days)
Median change in log10 HCV RNA
0
3
6
9
12
15
0
-1
-2
T mono (n=9)
PR (n=9)
T/PR (n=5)
-3
–3.66
-4
-5
–4.83
–5.51
-6
PROTON
Study Design
HCV GT1
24
12
Week 0
72
48
STOP
N=50
PSI-7977 200 mg QD
Peg-IFN + RBV
Peg-IFN + RBV
N=50
PSI-7977 400 mg QD
Peg-IFN + RBV
Peg-IFN + RBV
Non-RVR Peg-IFN + RBV
STOP
Non-RVR Peg-IFN + RBV
SVR
Follow-Up
Peg-IFN + RBV
N=25
125 treatment-naïve patients with HCV GT1
Planned 12 Week Interim analysis: Nelson, et al. EASL LB poster #1372
HCV GT2/GT3
12
Week 0
N=25
PSI-7977 400 mg QD
Peg-IFN + RBV
SVR12
25 treatment-naïve patients with HCV GT2/3
SVR24
PROTON
HCV GT2/GT3 Antiviral Responses
Week 2
n (evaluable)
HCV RNA <
LOD*
% Response
Lost to follow-up
% Response
(ITT)
Week 4
RVR
Week 12
cEVR/EOT
SVR12
24
24
24
24
21
24
24
24
88%
100%
100%
100%
1
1
1
1
84%
96%
96%
96%
*Roche COBAS TaqMan, LOD 15 IU/mL
PSI-7977 Electron study-GT 1/2/3
Electron study: concordance SVR12 /SVR 24
DEBIO 025 or Alispovir
Rice CM 2011
Alisporivir in GT-2/3: the VITAL study
phase IIb trial of alisporivir in treatment-naïve HCV GT-2 or GT-3 patients
ALV1000
n=83
Alisporivir 600 mg BID
Alisporivir 1000 mg QD*
ALV600R
n=84
Alisporivir 600 mg BID +
RBV
Alisporivir 600 mg QD +
RBV*
ALV800R
n=94
Alisporivir 600 mg BID +
RBV
Alisporivir 800 mg QD +
RBV*
ALV-P
n=39
Alisporivir 600 mg BID +
PegIFN
Alisporivir 600 mg QD +
PegIFN*
PR
n=40
PegIFN/RBV
Week
1
*Patients with HCV RNA ≥25 IU/mL at Week 4 received
alisporivir 600 mg QD + PegIFN/RBV from Week 6 until Week 24
24
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
26
Alisporivir in GT-2/3: the VITAL study
Patients with undetectable HCV RNA (%)
100
93 95 90 95
85
85
73
80
60
40
37
42
28
20
0
cEVR
RVR
ALV1000
ALV600R
ALV800R
ALV-P
PR
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
27
Conclusions
• HCV 2 infected represent up to 27% of
chronic pts
• PegIFN/RBV ensure rates of SVR up to
90% even after 12-16 weeks of treatment
• In HCV 2 pts, IL28B has an impact lower
than in HCV 1
• IFN free regimen might became a valuable
alternative to further reduce the Tx
duration
Thank you